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  • Review Article
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Infection, immune responses and the aetiology of childhood leukaemia

Nature Reviews Cancer volume 6, pages 193–203 (2006)Cite this article

Key Points

  • Childhood leukaemia is the most common paediatric cancer in developed societies.

  • The disease is biologically heterogeneous and no single or exclusive causal mechanism is likely.

  • The natural history of paediatric leukaemia usually involves pre-natal initiation of pre-leukaemic clones (frequently by chromosome translocation) followed by postnatal promotion, secondary mutation and overt disease. Latency after initiation can be very variable (a few months to 15 years).

  • Ionizing radiation is an accepted cause of leukaemia but not a significant cause. Non-ionizing radiation (for example, electromagnetic field radiation) seems to be a very weak or negligible cause.

  • Large, case–control epidemiology studies are required that incorporate biological subtypes of disease and inherited alleles associated with susceptibility. These studies also need to be driven by plausible biological hypotheses.

  • Two infection-based hypotheses have been proposed and assessed: Kinlen's 'population-mixing' hypothesis and Greaves' 'delayed-infection' hypothesis.

  • The body of epidemiological evidence now available is consistent with the view that many childhood leukaemias arise as a consequence of an abnormal immune response to common infection(s), but the mechanisms remain to be determined.

Abstract

Childhood leukaemia is the principal subtype of paediatric cancer and, despite success in treatment, its causes remain enigmatic. A plethora of candidate environmental exposures have been proposed, but most lack a biological rationale or consistent epidemiological evidence. Although there might not be a single or exclusive cause, an abnormal immune response to common infection(s) has emerged as a plausible aetiological mechanism.

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Figure 1: A 'minimal' model illustrating the crucial sequential events in the development of childhood leukaemia.
Figure 2: A model for infection-derived proliferative stress in the selection of pre-leukaemic cells.

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Acknowledgements

This review is dedicated to the memory of Professor Sir Richard Doll who chaired the UKCCS Management Committee and was a powerful advocate for epidemiological studies on childhood leukaemia. The author's research is supported by a specialist programme grant from the Leukaemia Research Fund and by The Kay Kendall Leukaemia Fund.

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  1. The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London, SW3 6JB, United Kingdom

    Mel Greaves

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DATABASES

National Cancer Institute

acute lymphoblastic leukaemia

acute myeloid leukaemia

Hodgkin lymphoma

non-Hodgkin lymphoma

Glossary

Non-homologous end-joining repair

Predominant, cellular mechanism for the repair of double-stranded DNA breaks; error-prone as no template sequence is used.

Time–space clustering

Increased incidence of cases in one place in a defined time period. This can occur by chance. A vivid illustration of this is the finding of statistically significant clusters in the United Kingdom in proximity to 'military sites' that turn out to be derelict medieval forts (R. Cartwright, personal communication).

Representative difference analysis

This method assesses whether there are any sequences in the DNA of patients' leukaemic cells that are not of endogenous origin and is based on subtracting leukaemic ('tester') DNA from constitutive or normal, non-leukaemic ('driver') DNA of the same individual.

T-helper (TH)1 and TH2 response

A TH1 cell-mediated immune response is mediated by pro-inflammatory cytokines such as interferon-γ, interleukin-1β and tumour-necrosis factor. It promotes cellular immune responses against intracellular infections and malignancy. A TH2 response involves production of cytokines, such as interleukin-4, that stimulate antibody production. TH2 cytokines promote secretory immune responses of mucosal surfaces to extracellular pathogens, and allergic reactions.

Aplasia

Defective production of red and white blood cells by the bone marrow.

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Greaves, M. Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer 6, 193–203 (2006). https://doi.org/10.1038/nrc1816

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